Malignant tumor (cancer) is one of the main diseases to seriously influence human health and threaten human life currently. More than 5 million people die of cancer all over the world every year. Although there already have some therapeutic means such as surgery, radiotherapy, chemotherapy and so on, their cure rate is generally not high. Wherein, the chemotherapy is the main treatment means, however it exists some deficiencies such as poor selectivity, severe side effects and the like. Therefore, it is becoming a research hotspot to find antitumor medicament having lower toxicity, mild side effect, higher anticancer activity and good stability, etc.
PI3K is a complicated large family, is also one of targets of targeting anti-tumor pharmaceutical, including type I, type II and type III. Type I of PI3K is divided into two subtypes as IA and IB, which respectively transmit signals from tyrosine kinase linked receptor and G protein linked receptor, and its effect is to catalyze phosphorylation of phosphatidyl inositol (P1) at D3 position, and convert substrate PIP2 into PIP3. P13K of Type IA is a dimer protein consist of catalytic subunit P110 and regulatory subunit P85, with double activities of lipoid kinase and protein kinase. The activity of P13K is strictly controlled by many mechanisms in normal cells. It is generally believed that inactive P85-P110 composition in resting cells is ubiquitous in cytoplasm, and waiting for appropriate signal to be activated. P13K is activated by two ways. Firstly, one of the two ways is to interact with growth factor receptor having phosphorylation tyrosine residues or to connexin, to cause conformational changes of P85-P110 dimers, and then P13K is activated. For RTK, the signal comes from activation of kinase mediated by ligand, to make tyrosine residues on the inner surface of the cell membrane produce phosphorylation. The tyrosine residues of phosphorylation immediately become binding sites of intracellular signaling proteins, and are activated by combinating with SH2 structure domain of P85 to make P85-P110 compounds gathered on the cell membrane, the second way is to combine Ras with P110 directly to make P13K activation.
After PI3K is activated, the second messenger PIPa is generated on cell membranes, PIPa is combined with a signal protein Akt containing PH structure domain and phosphoinositide dependent kinase-1 (PDK1) in cells, to make PDK1 phosphorylated Ser473 and Thr308 of Akt protein, and make Akt activation. Akt is also referred to as protein kinase B (PKB), is serine/threonine kinase with relative molecular mass of 60 000, and is a homologue of v-akt, and has the similarity with protein kinase A (PKA) and protein kinase C (PKC). Akt can directly phosphorylate various transcription factors, and can inhibit expression of apoptosis gene and enhance expression of anti-apoptotic gene by regulating the transcription factors, so as to promote cell survival. For example, transcription factor FKHRLI can promote transcription of apoptosis gene Fas-1 and Bim, Akt is transferred from cell membrane to cell nucleus and phosphorylates FKHRL1 after being activated. Phosphorylated FKHRL1 is transported out of the cell nucleus and chelated with cytoplasmic protein 14-3-3 together, and then lost transcription function to target genes. In addition, Akt can also positively regulate two transcription factors such as NF-κB and Bc1-2. NF-κB has something to do with cell differentiation, apoptosis and survival caused by many cytokines and growth factors. Under normal conditions, NF-κB is combined with its inhibitory factor I-κB in cytoplasm, and loses transcriptional activity. Akt can activate IKK (the kinase of 1-κB) by phosphorylation, and results in phosphorylation and, degradation of I-κB, and separates with NF-κB, and then the released NF-κB is translocated into the cell nucleus and induces expression of target gene. Akt1KK is necessary for mediating degradation of I-κB and activation of NF-κB, and is the key regulator in the process of NF-κB dependent gene transcription, and plays an important role in promoting tumor cell survival.
In addition to the expression of influencing apoptosis and anti-apoptotic genes, Akt can also promote cell survival directly by phosphorylating pro-apoptosis protein Bad. Bad is an apoptotic protein in EC1-2 family, and can promote cell apoptosis by combining and antagonising the Bc1-2 and the EC1-K. Akt can phosphorylate the Ser136 residues of Bad directly or by Raf-1 and P65PAK, to make the Bad chelate with the 14-3-3 protein in cytoplasm, to terminate the antagonism of Bad to the Bc1-2 or the Bc1-XI on mitochondrial membrane, and to make the released Bc1-2 or Bc1-XI restore the anti-apoptosis function. Besides, Akt can directly inhibit activities of cysteine aspartase-9 (caspase-9). Pro-caspase-9 loses its activity after being phosphorylated by Akt, and the downstream signal is interrupted.
WO0103456, WO2003072557, WO2005113554, WO2006122806, WO2006046040, WO2007044729, WO2008144463 and WO200911824 disclose compounds with PI3K inhibitors and antitumor activity thereof.
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